| Type of Document |
Master's Thesis |
| Author |
Isin, Emre M.
|
| Author's Email Address |
eisin@vt.edu |
| URN |
etd-11272000-120319 |
| Title |
Potential Prodrugs of the Neuronal Nitric Oxide Synthase and Monoamine Oxidase Inhibitor 7-Nitroindazole and Structurally Related Compounds |
| Degree |
Master of Science |
| Department |
Chemistry |
| Advisory Committee |
| Advisor Name |
Title |
| Dr. Neal Castagnoli, Jr. |
Committee Chair |
| Dr. David G.I. Kingston |
Committee Member |
| Dr. Harry C. Dorn |
Committee Member |
| Dr. James M. Tanko |
Committee Member |
|
| Keywords |
- SAR
- organic reaction mechanisms
- neuroprotection
- indazole
- tetrahydropyridinyl-based prodrugs
|
| Date of Defense |
2000-10-30 |
| Availability |
unrestricted |
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder of unknown cause that afflicts about 1.5 million Americans. The characteristic feature of PD is a deficiency of dopamine in the terminals of nigrostriatal neurons. Two enzyme systems, the neuronal form of nitric oxide synthase (nNOS) and monoamine oxidase B (MAO-B), have been linked to neurodegenerative pathways leading to PD. Several MAO-B and nNOS inhibitors have been evaluated for their neuroprotective properties in the mouse model of neurodegeneration which employs the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One such compound is 7-nitroindazole (7-NI), a compound which is reported to inhibit both enzymes.
This thesis focuses on the synthesis and biological evaluation of a potential prodrug form of 7-NI and related indazolyl containing compounds which are designed to release the active drugs following a metabolic bioactivation process. These studies have led to a detailed description of the nucleophilic aromatic substitution reactions between 4-chloro-1-methylpyridinium iodide and the indazolyl reactants that were employed as the initial step in the synthesis of the target compounds. The MAO-B substrate and inhibition properties of these “prodrugs” as well as the parent indazolyl compounds were examined. The results are discussed in relation to a previously developed active site model of MAO-B.
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| Files |
| Filename |
Size |
Approximate Download Time
(Hours:Minutes:Seconds)
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| 28.8 Modem |
56K Modem |
ISDN (64 Kb) |
ISDN (128 Kb) |
Higher-speed Access |
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1Main.pdf |
242.36 Kb |
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Chapter1-3.pdf |
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Chapter4.pdf |
1.47 Mb |
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Chapter5-7.pdf |
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